title: A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice.
abstract: Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small-molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex. Remarkably, CSP-TTK21 treatment promoted the formation of long and highly branched doublecortin-positive neurons in the subgranular zone of the dentate gyrus and reduced BrdU incorporation, suggesting that CBP/p300 activation favors maturation and differentiation of adult neuronal progenitors. In addition, mRNA levels of the neuroD1 differentiation marker and BDNF, a neurotrophin required for the terminal differentiation of newly generated neurons, were both increased in the hippocampus concomitantly with an enrichment of acetylated-histone on their proximal promoter. Finally, we found that CBP/p300 activation during a spatial training, while not improving retention of a recent memory, resulted in a significant extension of memory duration. This report is the first evidence for CBP/p300-mediated histone acetylation in the brain by an activator molecule, which has beneficial implications for the brain functions of adult neurogenesis and long-term memory. We propose that direct stimulation of acetyltransferase function could be useful in terms of therapeutic options for brain diseases.
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, and Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India.
authors.forename: Snehajyoti
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Pushpak
authors.initials: P
authors.lastname: Mizar
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Cassel
authors.forename: Romain
authors.initials: R
authors.lastname: Neidl
authors.forename: B Ruthrotha
authors.initials: BR
authors.lastname: Selvi
authors.forename: Dalvoy Vasudevarao
authors.initials: DV
authors.lastname: Mohankrishna
authors.forename: Bhusainahalli M
authors.initials: BM
authors.lastname: Vedamurthy
authors.forename: Anne
authors.initials: A
authors.lastname: Schneider
authors.forename: Olivier
authors.initials: O
authors.lastname: Bousiges
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathis
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Cassel
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Eswaramoorthy
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.forename: Anne-Laurence
authors.initials: AL
authors.lastname: Boutillier
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000254:growth & development; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism*; D002452:Cell Count; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D020536:Enzyme Activators / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000302:isolation & purification; D007150:Immunohistochemistry; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D054118:Nanospheres; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D000123:Acetyltransferases; D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D050882:CREB-Binding Protein; D020536:Enzyme Activators; D051548:Histone Acetyltransferases; D006657:Histones; D050880:p300-CBP Transcription Factors; C501008:Neurod1 protein, mouse; C084723:acetyl-CoA - lysine N6-acetyltransferase